Tricyclic taxanes having a butenyl substituted side-chain and pharmaceutical compositions containing them

ABSTRACT

Taxane derivatives having a 3&#39; butenyl substituted C13 side chain.

This invention was made with Government support under NIH Grant #CA42031 and NIH Grant #190 CA 55131 awarded by the National Institutes ofHealth. The Government has certain rights in the invention.

REFERENCE TO RELATED APPLICATIONS

This application is a divisional/application of U.S. Ser. No.08/463,704, filed Jun. 5, 1995, now U.S. Pat. No. 5,728,850 which is afile wrapper continuation application of U.S. Ser. No. 08/094,719 filedJul. 20, 1993, now abandoned which is a continuation-in-part applicationof U.S. Ser. No. 08/034,247 filed Mar. 22, 1993, now U.S. Pat. No.5,430,160, which is a continuation-in-part application of U.S. Ser. No.07/949,107, filed Sep. 22, 1992 now abandoned, which is acontinuation-in-part application of U.S. Ser. No. 07/863,849, filed Apr.6, 1992, now abandoned, which is a continuation-in-part application ofU.S. Ser. No. 07/862,955, filed Apr. 3, 1992, now abandoned, which is acontinuation-in-part application of U.S. Ser. No. 07/763,805, filed Sep.23, 1991, now abandoned. This application is also a continuation-in-partapplication of U.S. Ser. No. 07/975,705, filed Nov. 13, 1992, now U.S.Pat. No. 5,284,864, which is a continuation-in-part application of U.S.Ser. No. 07/949,107, filed Sep. 22, 1992, now abandoned which is acontinuation-in-part application of U.S. Ser. No. 07/863,849, filed Apr.6, 1992, now abandoned, which is a continuation-in-part application ofU.S. Ser. No. 07/862,955, filed Apr. 3, 1992, now abandoned, which is acontinuation-in-part application of U.S. Ser. No. 07/763,805, filed Sep.23, 1991, now abandoned.

BACKGROUND OF THE INVENTION

The present invention is directed to novel taxanes which have utility asantileukemia and antitumor agents.

The taxane family of terpenes, of which taxol is a member, has attractedconsiderable interest in both the biological and chemical arts. Taxol isa promising cancer chemotherapeutic agent with a broad spectrum ofantileukemic and tumor-inhibiting activity. Taxol has a 2'R, 3'Sconfiguration and the following structural formula: ##STR1## wherein Acis acetyl. Because of this promising activity, taxol is currentlyundergoing clinical trials in both France and the United States.

Colin et al. reported in U.S. Pat. No. 4,814,470 that taxol derivativeshaving structural formula (2) below, have an activity significantlygreater than that of taxol (1). ##STR2## R' represents hydrogen oracetyl and one of R" and R'" represents hydroxy and the other representstert-butoxycarbonylamino and their stereoisomeric forms, and mixturesthereof. The compound of formula (2) in which R' is hydrogen R" ishydroxy, R'" is tert-butoxycarbonylamino having the 2'R, 3'Sconfiguration is commonly referred to as taxotere.

Although taxol and taxotere are promising chemotherapeutic agents, theyare not universally effective. Accordingly, a need remains foradditional chemotherapeutic agents.

SUMMARY OF THE INVENTION

Among the objects of the present invention, therefore, is the provisionof novel taxane derivatives which are valuable antileukemia andantitumor agents.

Briefly, therefore, the present invention is directed to taxanederivatives having a C13 side chain which includes an alkyl substituent.In a preferred embodiment, the taxane derivative has a tricyclic ortetracyclic core and corresponds to the formula: ##STR3## wherein X₁ is--OX₆, --SX₇, or --NX₈ X₉ ;

X₂ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;

X₃ is hydrogen;

X₄ is butenyl;

X₅ is --COX₁₀, --COOX₁₀, --COSX₁₀, --CONX₈ X₁₀, or --SO₂ X₁₁ ;

X₆ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxyprotecting group, or a functional group which increases the watersolubility of the taxane derivative;

X₇ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydrylprotecting group;

X₈ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, orheterosubstituted alkyl, alkenyl, alkynyl, aryl or heteroaryl;

X₉ is an amino protecting group;

X₁₀ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterosubstitutedalkyl, alkenyl, alkynyl, aryl or heteroaryl;

X₁₁ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, --OX₁₀, or --NX₈ X₁₄ ;

X₁₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;

R₁ is hydrogen, hydroxy, protected hydroxy or together with R₁₄ forms acarbonate;

R₂ is hydrogen, hydroxy, --OCOR₃₁ or together with R_(2a) forms an oxo;

R_(2a) is hydrogen or taken together with R₂ forms an oxo;

R₄ is hydrogen, together with R_(4a) forms an oxo, oxirane or methylene,or together with R_(5a) and the carbon atoms to which they are attachedform an oxetane ring;

R_(4a) is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyano,hydroxy, --OCOR₃₀, or together with R₄ forms an oxo, oxirane ormethylene;

R₅ is hydrogen or together with R_(5a) forms an oxo,

R_(5a) is hydrogen, hydroxy, protected hydroxy, acyloxy, together withR₅ forms an oxo, or together with R₄ and the carbon atoms to which theyare attached form an oxetane ring;

R₆ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy,protected hydroxy or together with R_(6a) forms an oxo;

R_(6a) is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl,hydroxy, protected hydroxy or together with R₆ forms an oxo;

R₇ is hydrogen or together with R_(7a) forms an oxo,

R_(7a) is hydrogen, halogen, protected hydroxy, --OR₂₈, or together withR₇ forms an oxo;

R₉ is hydrogen or together with R_(9a) forms an oxo,

R_(9a) is hydrogen, hydroxy, protected hydroxy, acyloxy, or togetherwith R₉ forms an oxo;

R₁₀ is hydrogen or together with R_(10a) forms an oxo,

R_(10a) is hydrogen, --OCOR₂₉, hydroxy, or protected hydroxy, ortogether with R₁₀ forms an oxo;

R₁₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxy,protected hydroxy or together with R₁ forms a carbonate;

R_(14a) is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;

R₂₈ is hydrogen, acyl, hydroxy protecting group or a functional groupwhich increases the solubility of the taxane derivative; and

R₂₉, R₃₀, and R₃₁ are independently hydrogen, alkyl, alkenyl, alkynyl,monocyclic aryl or monocyclic heteroaryl.

Other objects and features of this invention will be in part apparentand in part pointed out hereinafter.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

As used herein "Ar" means aryl; "Ph" means phenyl; "Ac" means acetyl;"Et" means ethyl; "R" means alkyl unless otherwise defined; "Bu" meansbutyl; "Pr" means propyl; "TES" means triethylsilyl; "TMS" meanstrimethylsilyl; "TPAP" means tetrapropylammonium perruthenate; "DMAP"means p-dimethylamino pyridine; "DMF" means dimethylformamide; "LDA"means lithium diisopropylamide; "LHMDS" means lithiumhexamethyldisilazide; "LAH" means lithium aluminum hydride; "Red-Al"means sodium bis(2-methoxyethoxy) aluminum hydride; "AIBN" meansazo-(bis)-isobutyronitrile; "10-DAB" means 10-desacetylbaccatin III; FARmeans 2-chloro-1,1,2-trifluorotriethylamine; protected hydroxy means--OR wherein R is a hydroxy protecting group; sulfhydryl protectinggroup" includes, but is not limited to, hemithioacetals such as1-ethoxyethyl and methoxymethyl, thioesters, or thiocarbonates; "amineprotecting group" includes, but is not limited to, carbamates, forexample, 2,2,2-trichloroethylcarbamate or tertbutylcarbamate; and"hydroxy protecting group" includes, but is not limited to, ethers suchas methyl, t-butyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, allyl,trityl, methoxymethyl, 2-methoxypropyl, methoxyethoxymethyl,ethoxyethyl, tetrahydropyranyl, tetrahydrothiopyranyl, and trialkylsilylethers such as trimethylsilyl ether, triethylsilyl ether,dimethylarylsilyl ether, triisopropylsilyl ether andt-butyldimethylsilyl ether; esters such as benzoyl, acetyl,phenylacetyl, formyl, mono-, di-, and trihaloacetyl such aschloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl; andcarbonates including but not limited to alkyl carbonates having from oneto six carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl,t-butyl; isobutyl, and n-pentyl; alkyl carbonates having from one to sixcarbon atoms and substituted with one or more halogen atoms such as2,2,2-trichloroethoxymethyl and 2,2,2-trichloro-ethyl; alkenylcarbonates having from two to six carbon atoms such as vinyl and allyl;cycloalkyl carbonates having from three to six carbon atoms such ascyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; and phenyl orbenzyl carbonates optionally substituted on the ring with one or moreC₁₋₆ alkoxy, or nitro. Other hydroxyl, sulfhydryl and amine protectinggroups may be found in "Protective Groups in Organic Synthesis" by T. W.Greene, John Wiley and Sons, 1981.

The alkyl groups described herein, either alone or with the varioussubstituents defined herein are preferably lower alkyl containing fromone to six carbon atoms in the principal chain and up to 15 carbonatoms. They may be substituted, straight, branched chain or cyclic andinclude methyl, ethyl, propyl, isopropyl, butyl, hexyl, cyclopropyl,cyclopentyl, cyclohexyl and the like.

The alkenyl groups described herein, either alone or with the varioussubstituents defined herein are preferably lower alkenyl containing fromtwo to six carbon atoms in the principal chain and up to 15 carbonatoms. They may be substituted, straight or branched chain and includeethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and thelike.

The alkynyl groups described herein, either alone or with the varioussubstituents defined herein are preferably lower alkynyl containing fromtwo to six carbon atoms in the principal chain and up to 15 carbonatoms. They may be substituted, straight or branched chain and includeethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like.

The aryl moieties described herein, either alone or with varioussubstituents, contain from 6 to 15 carbon atoms and include phenyl.Substituents include alkanoxy, protected hydroxy, halogen, alkyl, aryl,alkenyl, acyl, acyloxy, nitro, amino, amido, etc. Phenyl is the morepreferred aryl.

The heteroaryl moieties described herein, either alone or with varioussubstituents, contain from 5 to 15 atoms and include, furyl, thienyl,pyridyl and the like. Substituents include alkanoxy, protected hydroxy,halogen, alkyl, aryl, alkenyl, acyl, acyloxy, nitro, amino, and amido.

The acyloxy groups described herein contain alkyl, alkenyl, alkynyl,aryl or heteroaryl groups.

The substituents of the substituted alkyl, alkenyl, alkynyl, aryl, andheteroaryl groups and moieties described herein, may be alkyl, alkenyl,alkynyl, aryl, heteroaryl and/or may contain nitrogen, oxygen, sulfur,halogens and include, for example, lower alkoxy such as methoxy, ethoxy,butoxy, halogen such as chloro or fluoro, nitro, amino, and keto.

In accordance with the present invention, it has been discovered thatcompounds corresponding to structural formula 3 show remarkableproperties, in vitro, and are valuable antileukemia and antitumoragents. Their biological activity has been determined in vitro, usingtubulin assays according to the method of Parness et al., J. CellBiology, 91: 479-487 (1981) and human cancer cell lines, and iscomparable to that exhibited by taxol and taxotere.

In one embodiment of the present invention, the substituents of thecyclic nucleus of the taxane (other than the C13 substituent) correspondto the substituents present on baccatin III or 10-DAB. That is, R₁₄ andR_(14a) are hydrogen, R₁₀ is hydrogen, R_(10a) is hydroxy or acetoxy, R₉and R_(9a) together form an oxo, R₇ is hydrogen, R_(7a) is hydroxy, R₅is hydrogen, R_(5a) and R₄ and the carbons to which they are attachedform an oxetane ring, R_(4a) is acetoxy, R₂ is hydrogen, R_(2a) isbenzoyloxy, and R₁ is hydroxy. In other embodiments, the taxane has astructure which differs from that of taxol or taxotere with respect tothe C13 side chain and at least one other substituent. For example, R₁₄may be hydroxy, R₂ may be hydroxy or --OCOR₃₁ wherein R₃₁ is hydrogen,alkyl or selected from the group comprising ##STR4## and Z is alkyl,hydroxy, alkoxy, halogen, or trifluoromethyl. R_(9a) may be hydrogen andR₉ may be hydrogen or hydroxy, R_(7a) may be hydrogen and R₇ may beacetoxy or other acyloxy or halogen, or R₁₀ and R_(10a) may each behydrogen or together form an oxo.

With respect to the C13 side-chain, in a preferred embodiment X₁ is--OH, X₂ is hydrogen, X₃ is hydrogen, X₄ is butenyl, X₅ is --COX₁₀ or--COOX₁₀, and X₁₀ is alkyl, alkenyl, alkynyl, aryl, furyl, thienyl orother heteroaryl and the taxane has the 2'R, 3'S configuration. In aparticularly preferred embodiment, X₄ is isobutenyl, X₅ is --COX₁₀ or--COOX₁₀ and X₁₀ is furyl, thienyl, alkyl substituted furyl or thienyl,pyridyl, tert-, iso- or n-butyl, ethyl, iso- or n-propyl, cyclopropyl,cyclohexyl, allyl, crotyl, 1,3-diethoxy-2-propyl, 2-methoxyethyl, amyl,neopentyl, PhCH₂ O--, --NPh₂, --NHnPr, --NHPh, or --NHEt.

Taxanes having the general formula 3 may be obtained by reacting aβ-lactam with alkoxides having the taxane tricyclic or tetracyclicnucleus and a C-13 metallic oxide substituent to form compounds having aβ-amido ester substituent at C-13. The β-lactams have the followingstructural formula: ##STR5## wherein X₁ -X₅ are as defined above.

The β-lactams can be prepared from readily available materials, as isillustrated in schemes A and B below: ##STR6## reagents: (a)triethylamine, CH₂ Cl₂, 25° C., 18 h; (b) 4 equiv ceric ammoniumnitrate, CH₃ CN, -10° C., 10 min; (c) KOH, THF, H₂ O, 0° C., 30 min, orpyrolidine, pyridine, 25° C., 3 h, (d) TESCl, pyridine, 25° C., 30 minor 2-methoxypropene toluene sulfonic acid (cat.), THF, 0° C., 2 h; (e)n-butyllithium, THF, -78° C., 30 min; and an acyl chloride orchloroformate (X₅ ═COX₁₀), sulfonyl chloride (X₅ =--COSX₁₀) orisocyanate (X₅ ═--CONX₈ X₁₀); (f) lithium diisopropyl amide, THF -78° C.to -50° C.; (g) lithium hexamethyldisilazide, THF --78° C. to 0° C.; (h)THF, -78° C. to 25° C., 12 h.

The starting materials are readily available. In scheme A, α-acetoxyacetyl chloride is prepared from glycolic acid, and, in the presence ofa tertiary amine, it cyclocondenses with imines prepared from aldehydesand p-methoxyaniline to give1-p-methoxyphenyl-3-acyloxy-4-arylazetidin-2-ones. The p-methoxyphenylgroup can be readily removed through oxidation with ceric ammoniumnitrate, and the acyloxy group can be hydrolyzed under standardconditions familiar to those experienced in the art to provide3-hydroxy-4-arylazetidin-2-ones. In Scheme B,ethyl-α-triethylsilyloxyacetate is readily prepared from glycolic acid.

In Schemes A and B, X₁ is preferably --OX₆ and X₆ is a hydroxyprotecting group. Protecting groups such as 2-methoxypropyl ("MOP"),1-ethoxyethyl ("EE") are preferred, but a variety of other standardprotecting groups such as the triethylsilyl group or other trialkyl (oraryl) silyl groups may be used. As noted above, additional hydroxyprotecting groups and the synthesis thereof may be found in "Protectivegroups in Organic Synthesis" by T. W. Greene, John Wiley & Sons, 1981.

The racemic β-lactams may be resolved into the pure enantiomers prior toprotection by recrystallization of the corresponding2-methoxy-2-(trifluoromethyl) phenylacetic esters. However, the reactiondescribed hereinbelow in which the β-amido ester side chain is attachedhas the advantage of being highly diastereoselective, thus permittingthe use of a racemic mixture of side chain precursor.

The alkoxides having the tricyclic or tetracyclic taxane nucleus and aC-13 metallic oxide or ammonium oxide substituent have the followingstructural formula: ##STR7## wherein R₁ -R_(14a) are as previouslydefined and M comprises ammonium or is a metal optionally selected fromthe group comprising Group IA, Group IIA and transition metals, andpreferably, Li, Mg, Na, K or Ti. Most preferably, the alkoxide has thetetracyclic taxane nucleus and corresponds to the structural formula:##STR8## wherein M, R₂, R_(4a), R₇, R_(7a), R₉, R_(9a), R₁₀, and R_(10a)are as previously defined.

The alkoxides can be prepared by reacting an alcohol having the taxanenucleus and a C-13 hydroxyl group with an organometallic compound in asuitable solvent. Most preferably, the alcohol is a protected baccatinIII, in particular, 7-O-triethylsilyl baccatin III (which can beobtained as described by Greene, et al. in JACS 110: 5917 (1988) or byother routes) or 7,10-bis-O-triethylsilyl baccatin III.

As reported in Greene et al., 10-deacetyl baccatin III is converted to7-O-triethylsilyl-10-deacetyl baccatin III according to the followingreaction scheme: ##STR9## Under what is reported to be carefullyoptimized conditions, 10-deacetyl baccatin III is reacted with 20equivalents of (C₂ H₅)₃ SiCl at 23° C. under an argon atmosphere for 20hours in the presence of 50 ml of pyridine/mmol of 10-deacetyl baccatinIII to provide 7-triethylsilyl-10-deacetyl baccatin III (4a) as areaction product in 84-86% yield after purification. The reactionproduct may then optionally be acetylated with 5 equivalents of CH₃ COCland 25 mL of pyridine/mmol of 4a at 0° C. under an argon atmosphere for48 hours to provide 86% yield of 7-O-triethylsilyl baccatin III (4b).Greene, et al. in JACS 110, 5917 at 5918 (1988).

The 7-protected baccatin III (4b) is reacted with an organometalliccompound such as LHMDS in a solvent such as tetrahydrofuran (THF), toform the metal alkoxide 13-O-lithium-7-O-triethylsilyl baccatin III asshown in the following reaction scheme: ##STR10##

As shown in the following reaction scheme,13-O-lithium-7-O-triethylsilyl baccatin III reacts with a β-lactam inwhich X₁ is preferably --OX₆, (X₆ being a hydroxy protecting group) andX₂ -X5 are as previously defined to provide an intermediate in which theC-7 and C-2' hydroxyl groups are protected. The protecting groups arethen hydrolyzed under mild conditions so as not to disturb the esterlinkage or the taxane substituents. ##STR11##

Both the conversion of the alcohol to the alkoxide and the ultimatesynthesis of the taxane derivative can take place in the same reactionvessel. Preferably, the β-lactam is added to the reaction vessel afterformation therein of the alkoxide.

Compounds of formula 3 of the instant invention are useful forinhibiting tumor growth in animals including humans and are preferablyadministered in the form of a pharmaceutical composition comprising aneffective antitumor amount of compound of the instant invention incombination with a pharmaceutically acceptable carrier or diluent.

Antitumor compositions herein may be made up in any suitable formappropriate for desired use; e.g., oral, parenteral or topicaladministration. Examples of parenteral administration are intramuscular,intravenous, intraperitoneal, rectal and subcutaneous administration.

The diluent or carrier ingredients should not be such as to diminish thetherapeutic effects of the antitumor compounds.

Suitable dosage forms for oral use include tablets, dispersible powders,granules, capsules, suspensions, syrups, and elixirs. Inert diluents andcarriers for tablets include, for example, calcium carbonate, sodiumcarbonate, lactose and talc. Tablets may also contain granulating anddisintegrating agents such as starch and alginic acid, binding agentssuch as starch, gelatin and acacia, and lubricating agents such asmagnesium stearate, stearic acid and talc. Tablets may be uncoated ormay be coated by unknown techniques; e.g., to delay disintegration andabsorption. Inert diluents and carriers which may be used in capsulesinclude, for example, calcium carbonate, calcium phosphate and kaolin.Suspensions, syrups and elixirs may contain conventional excipients, forexample, methyl cellulose, tragacanth, sodium alginate; wetting agents,such as lecithin and polyoxyethylene stearate; and preservatives, e.g.,ethyl- p-hydroxybenzoate.

Dosage forms suitable for parenteral administration include solutions,suspensions, dispersions, emulsions and the like. They may also bemanufactured in the form of sterile solid compositions which can bedissolved or suspended in sterile injectable medium immediately beforeuse. They may contain suspending or dispersing agents known in the art.

The water solubility of compounds of formula (3) may be improved bymodification of the C2' and/or C7 substituents. For instance, watersolubility may be increased if X₁ is --OX₆ and R_(7a) is --OR₂₈, and X₆and R₂₈ are independently hydrogen or --COGCOR¹ wherein

G is ethylene, propylene, --CH═CH--, 1,2-cyclohexane, or 1,2-phenylene,

R¹ =OH base, NR² R³, OR³, SR³, OCH₂ CONR⁴ R⁵, OH

R² =hydrogen, methyl

R³ =(CH₂)_(n) NR⁶ R⁷ ; (CH₂)_(n) N.sup.⊕ R⁶ R⁷ R⁸ X.sup.⊖

n=1 to 3

R⁴ =hydrogen, lower alkyl containing 1 to 4 carbons

R⁵ =hydrogen, lower alkyl containing 1 to 4 carbons, benzyl,hydroxyethyl, CH₂ CO₂ H, dimethylaminoethyl

R⁶ R⁷ =lower alkyl containing 1 or 2 carbons, benzyl or R⁶ and

R⁷ together with the nitrogen atom of NR⁶ R⁷ form the following rings##STR12## R⁸ =lower alkyl containing 1 or 2 carbons, benzylX.sup.⊖=halide

base=NH₃, (HOC₂ H₄)₃ N, N(CH₃)₃, CH₃ N(C₂ H₄ OH)₂, NH₂ (CH₂)₆ NH₂,N-methylglucamine, NaOH, KOH.

The preparation of compounds in which X₁ or X₂ is --COGCOR¹ is set forthin Haugwitz U.S. Pat. No. 4,942,184 which is incorporated herein byreference.

Alternatively, solubility may be increased when X₁ is --OX₆ and X₆ is aradical having the formula --COCX═CHX or --COX--CHX--CHX--SO₂ O--Mwherein X is hydrogen, alkyl or aryl and M is hydrogen, alkaline metalor an ammonio group as described in Kingston et al., U.S. Pat. No.5,059,699 (incorporated herein by reference).

Taxanes having alternative substituents may be prepared by selectivelyreducing the C9 Keto substituent to yield the corresponding C9 β-hydroxyderivative. The reducing agent is preferably a borohydride and, mostpreferably, tetrabutylammoniumborohydride (BU₄ NBH₄) ortriacetoxyborohydride.

As illustrated in Reaction Scheme 1, the reaction of baccatin III withBu₄ NBH₄ in methylene chloride yields 9-desoxo-9β-hydroxybaccatin III 5.After the C7 hydroxy group is protected with the triethylsilylprotecting group, for example, a suitable side chain may be attached to7-protected-9β-hydroxy derivative 6 as elsewhere described herein.Removal of the remaining protecting groups thus yields 9β-hydroxy-desoxotaxol or other 9β-hydroxytetracylic taxane having a C13 side chain.##STR13##

Alternatively, the C13 hydroxy group of 7-protected-9β-hydroxyderivative 6 may be protected with trimethylsilyl or other protectinggroup which can be selectively removed relative to the C7 hydroxyprotecting group as illustrated in Reaction Scheme 2, to enable furtherselective manipulation of the various substituents of the taxane. Forexample, reaction of 7,13-protected-9β-hydroxy derivative 7 with KHcauses the acetate group to migrate from C10 to C9 and the hydroxy groupto migrate from C9 to C10, thereby yielding 10-desacetyl derivative 8.Protection of the C10 hydroxy group of 10-desacetyl derivative 8 withtriethylsilyl yields derivative 9. Selective removal of the C13 hydroxyprotecting group from derivative 9 yields derivative 10 to which asuitable side chain may be attached as described above. ##STR14##

As shown in Reaction Scheme 3, 10-oxo derivative 11 can be provided byoxidation of 10-desacetyl derivative 8. Thereafter, the C13 hydroxyprotecting group can be selectively removed followed by attachment of aside chain as described above to yield 9-acetoxy-10-oxo-taxol or other9-acetoxy-10-oxotetracylic taxanes having a C13 side chain.Alternatively, the C9 acetate group can be selectively removed byreduction of 10-oxo derivative 11 with a reducing agent such as samariumdiiodide to yield 9-desoxo-10-oxo derivative 12 from which the C13hydroxy protecting group can be selectively removed followed byattachment of a side chain as described above to yield9-desoxo-10-oxo-taxol or other 9-desoxo-10-oxotetracylic taxanes havinga C13 side chain. ##STR15##

Reaction Scheme 4 illustrates a reaction in which 10-DAB is reduced toyield pentaol 13. The C7 and C10 hydroxyl groups of pentaol 13 can thenbe selectively protected with the triethylsilyl or another protectinggroup to produce triol 14 to which a C13 side chain can be attached asdescribed above or, alternatively, after further modification of thetetracylic substituents. ##STR16##

Taxanes having C9 and/or C10 acyloxy substituents other than acetate canbe prepared using 10-DAB as a starting material as illustrated inReaction Scheme 5. Reaction of 10-DAB with triethylsilyl chloride inpyridine yields 7-protected 10-DAB 15. The C10 hydroxy substituent of7-protected 10-DAB 15 may then be readily acylated with any standardacylating agent to yield derivative 16 having a new C10 acyloxysubstituent. Selective reduction of the C9 keto substituent ofderivative 16 yields 9β-hydroxy derivative 17 to which a C13 side chainmay be attached. Alternatively, the C10 and C9 groups can be caused tomigrate as set forth in Reaction Scheme 2, above. ##STR17##

Taxanes having alternative C2 and/or C4 esters can be prepared usingbaccatin III and 10-DAB as starting materials. The C2 and/or C4 estersof baccatin III and 10-DAB can be selectively reduced to thecorresponding alcohol(s) using reducing agents such as LAH or Red-Al,and new esters can thereafter be substituted using standard acylatingagents such as anhydrides and acid chlorides in combination with anamine such as pyridine, triethylamine, DMAP, or diisopropyl ethyl amine.Alternatively, the C2 and/or C4 alcohols may be converted to new C2and/or C4 esters through formation of the corresponding alkoxide bytreatment of the alcohol with a suitable base such as LDA followed by anacylating agent such as an acid chloride.

Baccatin III and 10-DAB analogs having different substituents at C2and/or C4 can be prepared as set forth in Reaction Schemes 6-10. Tosimplify the description, 10-DAB is used as the starting material. Itshould be understood, however, that baccatin III derivatives or analogsmay be produced using the same series of reactions (except for theprotection of the C10 hydroxy group) by simply replacing 10-DAB withbaccatin III as the starting material. 9-desoxo derivatives of thebaccatin III and 10-DAB analogs having different substituents at C2and/or C4 can then be prepared by reducing the C9 keto substituent ofthese analogs and carrying out the other reactions described above.

In Reaction Scheme 6, protected 10-DAB 3 is converted to the triol 18with lithium aluminum hydride. Triol 18 is then converted to thecorresponding C4 ester using Cl₂ CO in pyridine followed by anucleophilic agent (e.g., Grignard reagents or alkyllithium reagents).##STR18##

Deprotonation of triol 18 with LDA followed by introduction of an acidchloride selectively gives the C4 ester. For example, when acetylchloride was used, triol 18 was converted to 1,2 diol 4 as set forth inReaction Scheme 7.

Triol 18 can also readily be converted to the 1,2 carbonate 19.Acetylation of carbonate 19 under vigorous standard conditions providescarbonate 21 as described in Reaction Scheme 8; addition ofalkyllithiums or Grignard reagents to carbonate 19 provides the C2 esterhaving a free hydroxyl group at C4 as set forth in Reaction Scheme 6.##STR19##

As set forth in Reaction Scheme 9, other C4 substituents can be providedby reacting carbonate 19 with an acid chloride and a tertiary amine toyield carbonate 22 which is then reacted with alkyllithiums or Grignardreagents to provide 10-DAB derivatives having new substituents at C2.##STR20##

Alternatively, baccatin III may be used as a starting material andreacted as shown in Reaction Scheme 10. After being protected at C7 andC13, baccatin III is reduced with LAH to produce 1,2,4,10 tetraol 24.Tetraol 24 is converted to carbonate 25 using Cl₂ CO and pyridine, andcarbonate 25 is acylated at C10 with an acid chloride and pyridine toproduce carbonate 26 (as shown) or with acetic anhydride and pyridine(not shown). Acetylation of carbonate 26 under vigorous standardconditions provides carbonate 27 which is then reacted with alkyllithiums to provide the baccatin III derivatives having new substituentsat C2 and C10. ##STR21##

10-desacetoxy derivatives of baccatin III and 10-desoxy derivatives of10-DAB may be prepared by reacting baccatin III or 10-DAB (or theirderivatives) with samarium diiodide. Reaction between the tetracyclictaxane having a C10 leaving group and samarium diiodide may be carriedout at 0° C. in a solvent such as tetrahydrofuran. Advantageously, thesamarium diiodide selectively abstracts the C10 leaving group; C13 sidechains and other substituents on the tetracyclic nucleus remainundisturbed. Thereafter, the C9 keto substituent may be reduced toprovide the corresponding 9-desoxo-9β-hydroxy-10-desacetyoxy or10-desoxy derivatives as otherwise described herein.

C7 dihydro and other C7 substituted taxanes can be prepared as set forthin Reaction Schemes 11, 12 and 12a. ##STR22##

As shown in Reaction Scheme 12, Baccatin III may be converted into7-fluoro baccatin III by treatment with FAR at room temperature in THFsolution. Other baccatin derivatives with a free C7 hydroxyl groupbehave similarly. Alternatively, 7-chloro baccatin III can be preparedby treatment of baccatin III with methane sulfonyl chloride andtriethylamine in methylene chloride solution containing an excess oftriethylamine hydrochloride.

Taxanes having C7 acyloxy substituents can be prepared as set forth inReaction Scheme 12a, 7,13-protected 10-oxo-derivative 11 is converted toits corresponding C13 alkoxide by selectively removing the C13protecting group and replacing it with a metal such as lithium. Thealkoxide is then reacted with a β-lactam or other side chain precursor.Subsequent hydrolysis of the C7 protecting groups causes a migration ofthe C7 hydroxy substituent to C10, migration of the C10 oxo substituentto C9, and migration of the C9 acyloxy substituent to C7.

A wide variety of tricyclic taxanes are naturally occurring, and throughmanipulations analogous to those described herein, an appropriate sidechain can be attached to the C13 oxygen of these substances.Alternatively, as shown in Reaction Scheme 13, 7-O-triethylsilylbaccatin III can be converted to a tricyclic taxane through the actionof trimethyloxonium tetrafluoroborate in methylene chloride solution.The product diol then reacts with lead tetraacetate to provide thecorresponding C4 ketone. ##STR23##

Recently a hydroxylated taxane (14-hydroxy-10-deacetylbaccatin III) hasbeen discovered in an extract of yew needles (C&EN, p 36-37, Apr. 12,1993). Derivatives of this hydroxylated taxane having the various C2,C4, etc. functional groups described above may also be prepared by usingthis hydroxylated taxane. In addition, the C14 hydroxy group togetherwith the C1 hydroxy group of 10-DAB can be converted to a 1,2-carbonateas described in C&EN or it may be converted to a variety of esters orother functional groups as otherwise described herein in connection withthe C2, C4, C9 and C10 substituents.

The following examples are provided to more fully illustrate theinvention.

EXAMPLE 1 ##STR24## Preparation of 3'-desphenyl-3'-(2-methyl-1-propenyl)taxol

To a solution of 7-triethylsilyl baccatin III (120 mg, 0.171 mmol) in1.2 mL of THF at -45° C. was added dropwise 0.104 mL of a 1.63M solutionof nBuLi in hexane. After 0.5 h at -45° C., a solution ofcis-1-benzoyl-3-triethylsilyloxy-4-(2-methyl-1-propenyl)azetidin-2-one(295 mg, 0.885 mmol) in 1.2 mL of THF was added dropwise to the mixture.The solution was warmed to 0° C. and kept at that temperature for 1 hbefore 1 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 179 mg of amixture containing(2'R,3'S)-2',7-(bis)triethylsilyl-3'-desphenyl-3'-(2-methyl-1-propenyl)taxol and a small amount of the (2'S,3'R) isomer.

To a solution of 179 mg (0.171 mmol) of the mixture obtained from theprevious reaction in 11 mL of acetonitrile and 0.55 mL of pyridine at 0°C. was added 1.7 mL of 48% aqueous HF. The mixture was stirred at 0° C.for 3 h, then at 25° C. for 13 h, and partitioned between saturatedaqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethylacetate solution gave 140 mg of material which was purified by flashchromatography to give 109.0 mg (78%) of3'-desphenyl-3'-(2-methyl-1-propenyl) taxol, which was recrystallizedfrom methanol/water.

m.p.143-144° C.;[α]²⁵ _(Na) -61.0° (c 0.0065, CHCl₃).

¹ H NMR (CDCl₃, 300 MHz) δ8.11(d, J=7.1 Hz, 2H, benzoate ortho),7.69(d,J=8.3 Hz, 2H, benzamide ortho), 7.64-7.36(m, 6H, aromatic), 6.45(d,J=8.2 Hz, 1H, NH), 6.29(s, 1H, H10), 6.20 (dd, J=7.7, 7.7 Hz, 1H, H13),5.68(d, J=7.1 Hz, 1H, H2β), 5.46(m, 1H, vinyl), 5.27(ddd, J=8.8, 8.8,3.3 Hz, 1H, H3'), 4.96 (d, J=7.7 Hz, 1H, H5), 4.40(m, 1H, H7),4.36(m,1H, H2'), 4.32(d, J=7.8 Hz, 1H, H20α), 4.22 (d, J=7.8 Hz, 1H, H20β),3.82(d, J=7.1 Hz, 1H, H3), 3.63(d, J=6.6 Hz, 1H, 2'OH), 2.54(m, 1H,H6α), 2.48(d, J=3.9 Hz, 1H, 7OH), 2.42(m, 2H, H14), 2.39(s, 3H, 4Ac),2.23 (s, 3H, 10Ac), 2.16(br s, 3H, Me18), 1.89 (m, 1H, H6β), 1.88 (s,3H, Me19), 1.80(s, 4H, Me thienyl+1OH), 1.24(s, 3H, Me17), 1.14(s, 3H,Me16).

EXAMPLE 2 ##STR25## Preparation of3'-desphenyl-3'-isobutenyl-N-debenzoyl-N-(t-butoxycarbonyl) taxol

To a solution of 7-triethylsilyl baccatin III (30.0 mg, 0.043 mmol) in0.5 mL of THF at -45° C. was added dropwise 0.047 mL of a 1.0 M solutionof (TMS)₂ NLi in THF. After 0.5 h at -45° C., a solution ofcis-1-(t-butoxycarbonyl)-3-(2-methoxy-2-propoxy)-4-isobutenylazetidin-2-one(44.2 mg, 0.13 mmol) in 0.4 mL of THF was added dropwise to the mixture.The solution was warmed to 0° C. and kept at that temperature for 1 hbefore 1 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 40.3 mg of amixture containing(2'R,3'S)-2'-(2-methoxy-2-propoxy)-3'-desphenyl-3'-isobutenyl-7-triethylsilyl-N-debenzoyl-N-(t-butoxycarbonyl)taxol and a small amount of the (2'S,3'R) isomer.

To a solution of 40.3 mg (0.038 mmol) of the mixture obtained from theprevious reaction in 2 mL of acetonitrile and 0.1 mL of pyridine at 0°C. was added 0.3 mL of 48% aqueous HF. The mixture was stirred at 0° C.for 3 h, then at 25° C. for 13 h, and partitioned between saturatedaqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethylacetate solution gave 34.2 mg of material which was purified by flashchromatography to give 22.4 mg (72%) of3'-desphenyl-3'-isobutenyl-N-debenzoyl-N-(t-butoxycarbonyl) taxol, whichwas recrystallized from methanol/water.

m.p.147-149° C.; [α]²⁵ Na -65.2° (c 0.0023, CHCl₃).

¹ H NMR (CDCl₃, 300 MHz) δ8.11(d, J=7.1 Hz, 2H, benzoate ortho), 7.61(m,1H, benzoate para), 7.48 (m, 2H, benzoate meta), 6.45(s, 1H, NH),6.30(d, J=8.3 Hz, 1H, H10), 6.18 (dd, J=7.7, 7.7 Hz, 1H, H13), 5.68(d,J=7.1 Hz, 1H, H2β), 5.31(m, 1H, vinyl), 5.01(ddd, J=8.8, 8.8, 3.3 Hz,1H, H3'), 4.95 (d, J=7.7 Hz, 1H, H5), 4.76(m, 1H, H7),4.43(m, 1H, H2'),4.32(d, J=7.8 Hz, 1H, H20α), 4.19 (d, J=7.8 Hz, 1H, H20β), 3.81(d, J=7.1Hz, 1H, H3), 3.74(d, J=6.6 Hz, 1H, 2'OH), 2.54(m, 1H, H6α), 2.48(d,J=3.9 Hz, 1H, 7OH), 2.44(m, 2H, H14), 2.39(s, 3H, 4Ac), 2.26(s, 3H, Mevinyl), 2.25(s, 3H, Me vinyl), 2.23 (s, 3H, 10Ac), 1.98(br s, 3H, Me18),1.86 (m, 1H, H6β), 1.76 (s, 3H, Me19), 1.43(s, 9H, 3Me t-butoxy) 1.25(s,3H, Me17), 1.14(s, 3H, Me16).

EXAMPLE 3 ##STR26## Preparation ofN-debenzoyl-N-(n-butoxycarbonyl)-3'-desphenyl-3'-isobutenyl taxol

To a solution of 7-triethylsilyl baccatin III (70.0 mg, 0.086 mmol) in0.7 mL of THF at -45° C. was added dropwise 0.10 mL of a 1.0 M solutionof LiN(SiMe₃)₂ in hexane. After 0.5 h at -45° C., a solution ofcis-1-(n-butoxycarbonyl)-3-(2-methoxy-2-propoxy)-4-isobutenylazetidin-2-one (94.2 mg, 0.214 mmol) in 0.5 mL of THF was added dropwiseto the mixture. The solution was warmed to 0° C. and kept at thattemperature for 1 h before 1.0 mL of a 10% solution of AcOH in THF wasadded. The mixture was partitioned between saturated aqueous NaHCO₃ and60/40 ethyl acetate/hexane. Evaporation of the organic layer gave aresidue which was purified by filtration through silica gel to give 82.8mg of a mixture containing(2'R,3'S)-2'-(2-methoxy-2-propoxy)-7-triethylsilyl-N-debenzoyl-N-(n-butoxycarbonyl)-3'-desphenyl-3'-isobutenyltaxol and a small amount of the (2'S,3'R) isomer.

To a solution of 82.8 mg (0.083 mmol) of the mixture obtained from theprevious reaction in 6.0 mL of acetonitrile and 0.3 mL of pyridine at 0°C. was added 0.7 mL of 48% aqueous HF. The mixture was stirred at 0° C.for 3 h, then at 25° C. for 13 h, and partitioned between saturatedaqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethylacetate solution gave 67.7 mg of material which was purified by flashchromatography to give 53.2 mg (77%) ofN-debenzoyl-N-(n-butoxycarbonyl)-3'-desphenyl-3'-isobutenyl taxol, whichwas recrystallized from methanol/water.

m.p.132-134° C.; [α]²⁵ Na -64.0° (c 0.0023, CHCl₃).

¹ H NMR (CDCl₃, 300 MHz) δ8.11(d, J=7.2 Hz, 2H, benzoate ortho), 7.61(m,1H, benzoate para), 7.48(m, 2H, benzoate meta), 6.30(s, 1H, H10),6.21(dd, J=7.5, 7.5 Hz, 1H, H13), 5.67(d, J=7.2 Hz, 1H, H2β), 5.33(m,1H, olefine of isobutenyl), 4.97(d, J=7.8, 1H, H5), 4.91(d, J=8.2 Hz,1H, NH), 4.78(ddd, J=8.7, 8.7, 2.7 Hz, 1H, H3'), 4.43(m, 1H, H2'),4.31(d, J=7.8 Hz, 1H, H20α), 4.25(m, 1H, H7), 4.16(d, J=7.8 Hz, 1H,H20β), 3.96(q, J=6.6 Hz, 2H, n-butyloxy), 3.81(d, J=7.2 Hz, 1H, H3),3.34(d, J=6.6 Hz, 1H, 2'OH), 2.54(m, 1H, H6α), 2.50(d, J=3.9 Hz, 1H,7OH), 2.36(s, 3H, 4Ac), 2.33(m, 2H, H14), 2.26(s, 3H, 10Ac), 2.24(br s,3H, Me18), 1.89(s, 3H, Me19), 1.87(m, 1H, H6β), 1.77(s, 3H, Meisobutenyl), 1.75(s, 1H, 1OH), 1.68(s, 3H, Me isobutenyl), 1.56(m, 2H,n-butyloxy), 1.32(m, 2H, n-butyloxy), 1.26(s, 3H, Me17), 1.15(s, 3H,Me16), 0.85(t, J=6.6 Hz, 3H, Me of n-butyloxy).

EXAMPLE 4 ##STR27## Preparation of3'-desphenyl-3'-isobutenyl-N-debenzoyl-N-(isobutyloxycarbonyl) taxol

To a solution of 7-triethylsilyl baccatin III (40.0 mg, 0.042 mmol) in0.5 mL of THF at -45° C. was added dropwise 0.05 mL of a 1.0 M solutionof LiN(SiMe₃)₂ in hexane. After 0.5 h at -45° C., a solution ofcis-1-(isobutyloxycarbonyl)-3-(2-methoxy-2-propoxy)-4-isobutenylazetidin-2-one(43.0 mg, 0.13 mmol) in 0.5 mL of THF was added dropwise to the mixture.The solution was warmed to 0° C. and kept at that temperature for 1 hbefore 0.5 mL of a 10% solution of AcOH in THF was added. The mixturewas partitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 31.2 mg of amixture containing(2'R,3'S)-2'-(2methoxy-2-propoxy)-7-triethylsilyl-3'-desphenyl-3'-isobutenyl-N-debenzoyl-N-(isobutyloxycarbonyl)taxol and a small amount of the (2'S,3'R) isomer.

To a solution of 31.2 mg (0.030 mmol) of the mixture obtained from theprevious reaction in 2.0 mL of acetonitrile and 0.12 mL of pyridine at0° C. was added 0.25 mL of 48% aqueous HF. The mixture was stirred at 0°C. for 3 h, then at 25° C. for 13 h, and partitioned between saturatedaqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethylacetate solution gave 27.7 mg of material which was purified by flashchromatography to give 20.7 mg (83%) of3'-desphenyl-3'-isobutenyl-N-debenzoyl-N-(isobutyloxy-carbonyl) taxol,which was recrystallized from methanol/water.

m.p.147-148° C.; [α]²⁵ Na -58.2° (c 0.0016, CHCl₃)

¹ H NMR (CDCl₃, 300 MHz) δ8.11(d, J=7.2 Hz, 2H, benzoate ortho), 7.61(m,1H, benzoate para), 7.50(m, 2H, benzoate meta), 6.30(s, 1H, H10),6.22(dd, J=7.5, 7.5 Hz, 1H, H13), 5.65(d, J=7.2 Hz, 1H, H2β), 5.31(m,1H, olefine of isobuthenyl), 4.95(d, J=7.8, 1H, H5), 4.91(d, J=8.2 Hz,1H, NH), 4.76(ddd, J=8.7, 8.7, 2.7 Hz, 1H, H3'), 4.41(m, 1H, H2'),4.33(d, J=7.8 Hz, 1H, H20α), 4.25(m, 1H, H7), 4.16(d, J=7.8 Hz, 1H,H20β), 3.81(d, J=7.2 Hz, 1H, H3), 3.71(dd, J=10.2, 6.6 Hz, 1H,isobuthyl), 3.60(dd, J=10.2, 6.6 Hz, 1H, isobuthyl), 3.31(d, J=6.6 Hz,1H, 2'OH), 2.55(m, 1H, H6α), 2.50(d, J=3.9 Hz, 1H, 7OH), 2.37(s, 3H,4Ac), 2.31(m, 2H, H14), 2.26(s, 3H, 10Ac), 2.23(br s, 3H, Me18), 1.89(s,3H, Me19), 1.87(m, 1H, H6β), 1.77(s, 3H, Me isobuthenyl), 1.75(s, 1H,1OH), 1.66(s, 3H, Me isobuthenyl), 1.25(s, 3H, Me17), 1.15(s, 3H, Me16),0.76(d, J=7.2 Hz, 3H, Me of isobuthyl), 0.70(d, J=6.6 Hz, 3H, Me ofisobuthyl).

EXAMPLE 5 ##STR28## Preparation of3'-desphenyl-3'-isobutenyl-N-debenzoyl-N-(ethoxycarbonyl) taxol

To a solution of 7-triethylsilyl baccatin III (100.0 mg, 0.142 mmol) in1.0 mL of THF at -45° C. was added dropwise 0.16 mL of a 1.0 M solutionof LiN(SiMe₃)₂ in hexane. After 0.5 h at -45° C., a solution ofcis-1-(ethoxycarbonyl)-3-(2'-2"-(2-methoxy-2-propoxy)-4-isobutenylazetidin-2-one(155 mg, 0.43 mmol) in 1.0 mL of THF was added dropwise to the mixture.The solution was warmed to 0° C. and kept at that temperature for 1 hbefore 1.0 mL of a 10% solution of AcOH in THF was added. The mixturewas partitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 112.2 mg of amixture containing(2'R,3'S)-2'-(2-methoxy-2-propoxy)-3'-desphenyl-3'-isobutenyl-7-triethylsilyl-N-debenzoyl-N-(ethoxycarbonyl)taxol and a small amount of the (2'S,3'R) isomer.

To a solution of 112.2 mg (0.109 mmol) of the mixture obtained from theprevious reaction in 7.0 mL of acetonitrile and 0.4 mL of pyridine at 0°C. was added 0.9 mL of 48% aqueous HF. The mixture was stirred at 0° C.for 3 h, then at 25° C. for 13 h, and partitioned between saturatedaqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethylacetate solution gave 98.7 mg of material which was purified by flashchromatography to give 81.4 mg (93%) of3'-desphenyl-3'-isobutenyl-N-debenzoyl-N-(ethoxycarbonyl) taxol, whichwas recrystallized from methanol/water.

m.p.137-140° C.; [α]²⁵ Na -56.2.0° (c 0.0023, CHCl₃)

¹ H NMR (CDCl₃, 300 MHz) δ8.11(d, J=7.2 Hz, 2H, benzoate ortho), 7.61(m,1H, benzoate para), 7.50(m, 2H, benzoate meta), 6.30(s, 1H, H10),6.19(dd, J=7.5, 7.5 Hz, 1H, H13), 5.65(d, J=7.2 Hz, 1H, H2β), 5.31(m,1H, olefine of isobuthenyl), 4.98(d, J=7.8, 1H, H5), 4.90(d, J=8.2 Hz,1H, NH), 4.75(ddd, J=8.7, 8.7, 2.7 Hz, 1H, H3'), 4.45(m, 1H, H2'),4.31(d, J=7.8 Hz, 1H, H20α), 4.25(m, 1H, H7), 4.16(d, J=7.8 Hz, 1H,H20β), 3.93(q, J=7.2 Hz, 2H, ethyl), 3.81(d, J=7.2 Hz, 1H, H3), 3.34(d,J=6.6 Hz, 1H, 2'OH), 2.54(m, 1H, H6α), 2.50(d, J=3.9 Hz, 1H, 7OH),2.36(s, 3H, 4Ac), 2.33(m, 2H, H14), 2.26(s, 3H, 10Ac), 2.24(br s, 3H,Me18), 1.89(s, 3H, Me19), 1.87(m, 1H, H6β), 1.78(s, 3H, Me isobuthenyl),1.73(s, 1H, 1OH), 1.68(s, 3H, Me isobuthenyl), 1.26(s, 3H, Me17),1.15(s, 3H, Me16), 1.08(t, J=7.2 Hz, 3H, Me of ethyl).

EXAMPLE 6 ##STR29## Preparation of3'-desphenyl-3'-isobutenyl-N-debenzoyl-N-(neopentyloxycarbonyl) taxol

To a solution of 7-triethylsilyl baccatin III (50.0 mg, 0.071 mmol) in0.7 mL of THF at -45° C. was added dropwise 0.08 mL of a 1.0 M solutionof LiN(SiMe₃)₂ in hexane. After 0.5 h at -45° C., a solution ofcis-1-(neopentyloxycarbonyl)-3-(2-methoxy-2-propoxy)-4-isobuthenylazetidin-2-one(68.9 mg, 0.21 mmol) in 1.0 mL of THF was added dropwise to the mixture.The solution was warmed to 0° C. and kept at that temperature for 1 hbefore 1.0 mL of a 10% solution of AcOH in THF was added. The mixturewas partitioned between saturated aqueous NaHCO, and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 65.1 mg of amixture containing(2'R,3'S)-2'-(2-methoxy-2-propoxy)-3'-desphenyl-3'-isobutenyl-7-triethylsilyl-N-debenzoyl-N-(neopentyloxycarbonyl)taxol and a small amount of the (2'S,3'R) isomer.

To a solution of 65.1 mg (0.057 mmol) of the mixture obtained from theprevious reaction in 6.0 mL of acetonitrile and 0.3 mL of pyridine at 0°C. was added 0.7 mL of 48% aqueous HF. The mixture was stirred at 0° C.for 3 h, then at 25° C. for 13 h, and partitioned between saturatedaqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethylacetate solution gave 58.2 mg of material which was purified by flashchromatography to give 31.2 mg (65%) of3'-desphenyl-3'-(isobutenyl)-N-debenzoyl-N-(neopentyloxycarbonyl) taxol,which was recrystallized from methanol/water.

m.p.147-149° C.; [α]²⁵ Na -58.5° (c 0.0019, CHCl₃).

¹ H NMR (CDCl₃, 300 MHz) δ8.15(d, J=7.2 Hz, 2H, benzoate ortho), 7.61(m,1H, benzoate para), 7.50(m, 2H, benzoate meta), 6.30(s, 1H, H10),6.22(dd, J=7.5, 7.5 Hz, 1H, H13), 5.68(d, J=7.2 Hz, 1H, H2β), 5.32(m,1H, olefine of isobuthenyl), 4.98(d, J=7.8, 1H, H5), 4.89(d, J=8.2 Hz,1H, NH), 4.76(ddd, J=8.7, 8.7, 2.7 Hz, 1H, H3'), 4.43(m, 1H, H2'),4.29(d, J=7.8 Hz, 1H, H20α), 4.25(m, 1H, H7), 4.16(d, J=7.8 Hz, 1H,H20β), 3.76(s, 2H, neopenthyloxy), 3.81(d, J=7.2 Hz, 1H, H3), 3.34(d,J=6.6 Hz, 1H, 2'OH), 2.55(m, 1H, H6α), 2.50(d, J=3.9 Hz, 1H, 7OH),2.33(s, 3H, 4Ac), 2.30(m, 2H, H14), 2.26(s, 3H, 10Ac), 2.24(br s, 3H,Me18), 1.89(s, 3H, Me19), 1.87(m, 1H, H6β), 1.77(s, 3H, Me isobuthenyl),1.75(s, 1H, 1OH), 1.68(s, 3H, Me isobuthenyl), 1.26(s, 3H, Me17),1.20(s, 9H, Me of neopenthyloxy) 1.15(s, 3H, Me16).

EXAMPLE 7 ##STR30## Preparation of3'-desphenyl-3'-isobutenyl-N-debenzoyl-N-(isopropyloxycarbonyl) taxol

To a solution of 7-triethylsilyl baccatin III (50.0 mg, 0.071 mmol) in0.7 mL of THF at -45° C. was added dropwise 0.08 mL of a 1.0 M solutionof LiN(SiMe₃)₂ in hexane. After 0.5 h at -45° C., a solution ofcis-1-(isopropyloxycarbonyl)-3-(2-methoxy-2-propoxy)-4-isobutenylazetidin-2-one(56.3 mg, 0.22 mmol) in 1.0 mL of THF was added dropwise to the mixture.The solution was warmed to 0° C. and kept at that temperature for 1 hbefore 1.0 mL of a 10% solution of AcOH in THF was added. The mixturewas partitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 63.4 mg of amixture containing(2'R,3'S)-2'-(2-methoxy-2-propoxy)-3'-desphenyl-3'-isobutenyl-7-triethylsilyl-N-debenzoyl-N-(isopropyloxycarbonyl)taxol and a small amount of the (2'S,3'R) isomer.

To a solution of 63.4 mg (0.057 mmol) of the mixture obtained from theprevious reaction in 5.5 mL of acetonitrile and 0.3 mL of pyridine at 0°C. was added 0.66 mL of 48% aqueous HF. The mixture was stirred at 0° C.for 3 h, then at 25° C. for 13 h, and partitioned between saturatedaqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethylacetate solution gave 49.2 mg of material which was purified by flashchromatography to give 38.2 mg (82%) of3'-desphenyl-3'-isobutenyl-N-debenzoyl-N-(isopropyloxycarbonyl) taxol,which was recrystallized from methanol/water.

m.p.145-147° C.; [α]²⁵ Na -58.3° (c 0.0019, CHCl₃).

¹ H NMR (CDCl₃, 300 MHz) δ8.12(d, J=7.2 Hz, 2H, benzoate ortho), 7.61(m,1H, benzoate para), 7.50(m, 2H, benzoate meta), 6.30(s, 1H, H10),6.20(dd, J=7.5, 7.5 Hz, 1H, H13), 5.65(d, J=7.2 Hz, 1H, H2β), 5.31(m,1H, olefine of isobuthenyl), 4.96(d, J=7.8, 1H, H5), 4.90(d, J=8.2 Hz,1H, NH), 4.77(ddd, J=8.7, 8.7, 2.7 Hz, 1H, H3'), 4.69(m, 1H,isopropyloxy), 4.43(m, 1H, H2'), 4.31(d, J=7.8 Hz, 1H, H20α), 4.24(m,1H, H7), 4.15(d, J=7.8 Hz, 1H, H20β), 3.81(d, J=7.2 Hz, 1H, H3), 3.33(d,J=6.6 Hz, 1H, 2'OH), 2.54(m, 1H, H6α), 2.50(d, J=3.9 Hz, 1H, 7OH),2.34(s, 3H, 4Ac), 2.30(m, 2H, H14), 2.24(s, 3H, 10Ac), 2.21(br s, 3H,Me18), 1.88(s, 3H, Me19), 1.87(m, 1H, H6β), 1.77(s, 3H, Me isobuthenyl),1.75(s, 1H, 1OH), 1.66(s, 3H, Me isobuthenyl), 1.25(s, 3H, Me17),1.16(s, 3H, Me16), 1.14(d, J=6.6Hz, 3H, Me of isopropyloxy), 1.12(d,J=6.6 Hz, 3H, Me of isopropyloxy).

EXAMPLE 8 ##STR31## Preparation of3'-desphenyl-3'-isobutenyl-N-debenzoyl-N-(allyloxycarbonyl) taxol

To a solution of 7-triethylsilyl baccatin III (50.0 mg, 0.071 mmol) in0.7 mL of THF at -45° C. was added dropwise 0.08 mL of a 1.0 M solutionof LiN(SiMe₃)₂ in hexane. After 0.5 h at -45° C., a solution ofcis-1-(allyloxycarbonyl)-3-(2-methoxy-2-propoxy)-4-isobutenylazetidin-2-one(65.4 mg, 0.22 mmol) in 1.0 mL of THF was added dropwise to the mixture.The solution was warmed to 0° C. and kept at that temperature for 1 hbefore 1.0 mL of a 10% solution of AcOH in THF was added. The mixturewas partitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 64.4 mg of amixture containing(2'R,3'S)-2'-(2-methoxy-2-propoxy)-3'-desphenyl-3'-isobuthenyl-7-triethylsilyl-N-debenzoyl-N-(allyloxycarbonyl)taxol and a small amount of the (2'S,3'R) isomer.

To a solution of 64.4 mg (0.058 mmol) of the mixture obtained from theprevious reaction in 6.0 mL of acetonitrile and 0.28 mL of pyridine at0° C. was added 0.7 mL of 48% aqueous HF. The mixture was stirred at 0°C. for 3 h, then at 25° C. for 13 h, and partitioned between saturatedaqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethylacetate solution gave 53.2 mg of material which was purified by flashchromatography to give 33.3 mg (71%) of3'-desphenyl-3'-isobutenyl-N-debenzoyl-N-(allyloxycarbonyl) taxol, whichwas recrystallized from methanol/water.

m.p.137-139° C.; [α]²⁵ Na -59.1° (c 0.0022, CHCl₃).

¹ H NMR (CDCl₃, 300 MHz) δ8.11(d, J=7.2 Hz, 2H, benzoate ortho), 7.60(m,1H, benzoate para), 7.50(m, 2H, benzoate meta), 6.29(s, 1H, H10),6.21(dd, J=7.5, 7.5 Hz, 1H, H13), 5.78(m, 1H, allyl), 5.67(d, J=7.2 Hz,1H, H2β), 5.33(m, 1H, olefine of isobuthenyl), 5.14(m, 2H, allyl),4.97(d, J=7.8, 1H, H5), 4.91(d, J=8.2 Hz, 1H, NH), 4.78(ddd, J=8.7, 8.7,2.7 Hz, 1H, H3'), 4.43(m, 1H, H2'), 4.31(d, J=7.8 Hz, 1H, H20α), 4.25(m,1H, H7), 4.18(d, J=7.8 Hz, 1H, H20β), 4.08(d, J=6.6 Hz, 2H, allyl)3.79(d, J=7.2 Hz, 1H, H3), 3.34(d, J=6.6 Hz, 1H, 2'OH), 2.55(m, 1H,H6α), 2.50(d, J=3.9 Hz, 1H, 7OH), 2.36(s, 3H, 4Ac), 2.33(m, 2H, H14),2.26(s, 3H, 10Ac), 2.24(br s, 3H, Me18), 1.88(s, 3H, Me19), 1.85(m, 1H,H6β), 1.72(s, 3H, Me isobuthenyl), 1.69(s, 1H, 1OH), 1.61(s, 3H, Meisobuthenyl), 1.25(s, 3H, Me17), 1.15(s, 3H, Me16).

EXAMPLE 9 ##STR32## Preparation of3'-desphenyl-3'-isobutenyl-N-debenzoyl-N-(benzyloxycarbonyl) taxol

To a solution of 7-triethylsilyl baccatin III (50.0 mg, 0.071 mmol) in0.7 mL of THF at -40° C. was added dropwise 0.08 mL of a 1.0 M solutionof LiN(SiMe₃)₂ in hexane. After 0.5 h at -4° C., a solution ofcis-1-(benzyloxycarbonyl)-3-(2-methoxy-2-propoxy)-4-isobutenylazetidin-2-one(63 mg, 0.21 mmol) in 0.5 mL of THF was added dropwise to the mixture.The solution was warmed to 0° C. and kept at that temperature for 1 hbefore 1.0 mL of a 10% solution of AcOH in THF was added. The mixturewas partitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 60.4 mg of amixture containing(2'R,3'S)-2'-(2-methoxy-2-propoxy)-3'-desphenyl-3'-isobutenyl-7-triethylsilyl-N-debenzoyl-N-(benzyloxycarbonyl)taxol and a small amount of the (2'S,3'R) isomer.

To a solution of 60.4 mg (0.053 mmol) of the mixture obtained from theprevious reaction in 5.0 mL of acetonitrile and 0.3 mL of pyridine at 0°C. was added 0.65 mL of 48% aqueous HF. The mixture was stirred at 0° C.for 3 h, then at 25° C. for 13 h, and partitioned between saturatedaqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethylacetate solution gave 48.2 mg of material which was purified by flashchromatography to give 34.1 mg (74%) of3'-desphenyl-3'-isobutenyl-N-debenzoyl-N-(benzyloxycarbonyl) taxol,which was recrystallized from methanol/water.

m.p.148-149° C.; [α]²⁵ Na -53.2.0° (c 0.0026, CHCl₃).

¹ H NMR (CDCl₃, 300 MHz) δ8.15(d, J=7.2 Hz, 2H, benzoate ortho), 7.61(m,1H, benzoate para), 7.48(m, 2H, benzoate meta), 7.22-7.20 (m, 3H,benzyl), 7.10-7.05(m, 2H, benzyl), 6.29(s, 1H, H10), 6.21(dd, J=7.5, 7.5Hz, 1H, H13), 5.63(d, J=7.2 Hz, 1H, H2b), 5.33(m, 1H, olefine ofisobuthenyl), 5.06(d, J=12.3 Hz, 1H, benzyl), 4.97(d, J=7.8, 1H, H5),4.91(d, J=8.2 Hz, 1H, NH), 4.85(d, J=12.3 Hz, 1H, benzyl), 4.76(ddd,J=8.7, 8.7, 2.7 Hz, 1H, H3'), 4.48(m, 1H, H2'), 4.30(d, J=7.8 Hz, 1H,H20α), 4.25(m, 1H, H7), 4.16(d, J=7.8 Hz, 1H, H20β), 3.81(d, J=7.2 Hz,1H, H3), 3.34(d, J=6.6 Hz, 1H, 2'OH), 2.55(m, 1H, H6α), 2.49(d, J=3.9Hz, 1H, 7OH), 2.36(s, 3H, 4Ac), 2.32(m, 2H, H14), 2.27(s, 3H, 10Ac),2.24(br s, 3H, Me18), 1.90(s, 3H, Me19), 1.86(m, 1H, H6β), 1.77(s, 3H,Me isobuthenyl), 1.75(s, 1H, 1OH), 1.67(s, 3H, Me isobuthenyl), 1.27(s,3H, Me17), 1.16(s, 3H, Me16).

EXAMPLE 10 ##STR33## Preparation of3'-desphenyl-3'-isobutenyl-N-debenzoyl-N-(trimethylsilylmethoxycarbonyl)taxol

To a solution of 7-triethylsilyl baccatin III (50.0 mg, 0.71 mmol) in0.7 mL of THF at -45° C. was added dropwise 0.08 mL of a 1.0 M solutionof LiN(SiMe₃)₂ in hexane. After 0.5 h at -45° C., a solution ofcis-1-(trimethylsilylmethoxycarbonyl)-3-(2-methoxy-2-propoxy)-4-(isobuthenyl)azetidin-2-one(77.0 mg, 0.22 mmol) in 0.7 mL of THF was added dropwise to the mixture.The solution was warmed to 0° C. and kept at that temperature for 1 hbefore 1.0 mL of a 10% solution of AcOH in THF was added. The mixturewas partitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 58.4 mg of amixture containing(2'R,3'S)-2'-(2-methoxy-2-propoxy)-3'-desphenyl-3'-isobutenyl-7-triethylsilyl-N-debenzoyl-N-(trimethylsilylmethoxycarbonyl)taxol and a small amount of the (2'S,3'R) isomer.

To a solution of 58.4 mg (0.51 mmol) of the mixture obtained from theprevious reaction in 5.0 mL of acetonitrile and 0.30 mL of pyridine at0° C. was added 0.60 mL of 48% aqueous HF. The mixture was stirred at 0°C. for 3 h, then at 25° C. for 13 h, and partitioned between saturatedaqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethylacetate solution gave 51.2 mg of material which was purified by flashchromatography to give 31.1 mg (71%) of3'-desphenyl-3'-isobutenyl-N-debenzoyl-N-(trimethylsilylmethoxycarbonyl)taxol, which was recrystallized from methanol/water.

m.p.149-151° C.; [α]²⁵ Na -58.0° (c 0.0018, CHCl₃).

¹ H NMR (CDCl₃, 300 MHz) δ8.11(d, J=7.2 Hz, 2H, benzoate ortho), 7.61(m,1H, benzoate para), 7.48(m, 2H, benzoate meta), 6.30(s, 1H, H10),6.21(dd, J=7.5, 7.5 Hz, 1H, H13), 5.67(d, J=7.2 Hz, 1H, H2β), 5.33(m,1H, olefine of isobuthenyl), 4.97(d, J=7.8, 1H, H5), 4.88(d, J=8.2 Hz,1H, NH), 4.76(ddd, J=8.7, 8.7, 2.7 Hz, 1H, H3'), 4.41(m, 1H, H2'),4.28(d, J=7.8 Hz, 1H, H20α), 4.25(m, 1H, H7), 4.16(d, J=7.8 Hz, 1H,H20β), 3.76(d, J=7.2 Hz, 1H, H3), 3.68(d, J=14.1 Hz, 1H, CH₂ TMS),3.51(d, J=14.1 Hz, 1H, CH₂ TMS), 3.41(d, J=6.6 Hz, 1H, 2'OH), 2.55(m,1H, H6α), 2.50(d, J=3.9 Hz, 1H, 7OH), 2.29(s, 3H, 4Ac), 2.25(m, 2H,H14), 2.21(s, 3H, 10Ac), 2.24(br s, 3H, Me18), 1.89(s, 3H, Me19),1.87(m, 1H, H6β), 1.77(s, 3H, Me isobuthenyl), 1.75(s, 1H, 1OH), 1.68(s,3H, Me isobuthenyl), 1.18(s, 3H, Me17), 1.15(s, 3H, Me16), -0.04(s, 9H,Me₃ Si--).

EXAMPLE 11 ##STR34## Preparation of3'-desphenyl-3'-(isobutenyl)-N-desbenzoyl-N-(t-butoxycarbonyl)-9-desoxo-9.beta.-hydroxy-10-desacetyltaxol

To a solution of7,10-(bis)-O-triethylsilyl-9-desoxo-9β-hydroxy-10-deacetyl baccatin(III) (70.0 mg, 0.09 mmol) in 1.0 mL of THF at -45° C. was addeddropwise 0.10 mL of a 0.98 M solution of LiN(SiMe₃)₂ in hexane. After0.5 h at -45° C., a solution ofcis-1-(t-butoxycarbonyl)-3-(2-methoxyisopropyloxy)-4-(isobutenyl)azetidin-2-one(84.5 mg, 0.27 mmol) in 1.0 mL of THF was added dropwise to the mixture.The solution was warmed to 0° C. and kept at that temperature for 1 hbefore 1 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 88.3 mg of amixture containing (2'R,3'S)-2',7,10-(tris)-O-triethylsilyl-3'-desphenyl-3'-(isobutenyl)-N-desbenzoyl-N-(t-butoxycarbonyl)-9-desoxo-9β-hydroxy-10-desacetyltaxol and a small amount of the (2'S,3'R) isomer.

To a solution of 88.3 mg (0.080 mmol) of the mixture obtained from theprevious reaction in 13.5 mL of acetonitrile and 0.55 mL of pyridine at0° C. was added 1.90 mL of 48% aqueous HF. The mixture was stirred at 0°C. for 3 h, then at 25° C. for 13 h, and partitioned between saturatedaqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethylacetate solution gave 67.2 mg of material which was purified by flashchromatography to give 52.7 mg (82%) of3'-desphenyl-3'-(isobutenyl)-N-desbenzoyl-N-(t-butoxycarbonyl)-9-desoxo-9.beta.-hydroxy-10-desacetyltaxol, which was recrystallized from methanol/water.

m.p.138-140° C.; [α]²⁵ Na -55.2° (c 0.0026, CHCl₃)

¹ H NMR (MeOH, 300 MHz) δ8.11(d, J=7.1 Hz, 2H, benzoate ortho), 7.61(m,1H, benzoate para), 7.48(m, 2H, benzoate meta), 6.13(m, 1H, H13),6.12(m, 1H, H2), 5.21(br s., 1H, H3'), 5.02(d, J=5.3 Hz, 1H, H10),4.93(d, J=8.1 Hz, 1H, H5), 4.85(d, J=9.1 Hz, 1H, NH), 4.84(d, J=8.5 Hz,1H, Me₂ C═CH--), 4.50(br s, 1H, H2'), 4.50(d, J=5.5 Hz, 1H, H9), 4.22(d,J=8.1, 1H, H20α), 4.18(d, J=8.1 Hz, 1H, H20β), 3.89(dd, J=9.4, 7.5 Hz,1H, H7), 3.12(d, J=5.5 Hz, H3), 2.45(m, 1H, H6α), 2.31(m, 1H, H14α),2.29(s, 3H, 4Ac), 2.18(m, 1H, H14β), 1.85(ddd, J=15.1, 9.4, 1.2 Hz,H6β), 1.81(s, 3H, Me16), 1.76(s, 3H, Me18), 1.72(s, 6H, 2Me fromisobuthenyl), 1.61(s, 3H, Me19), 1.39(s, 9H, 3Me t-buthoxy), 1.26(s, 3H,Me17).

EXAMPLE 12 ##STR35## Preparation of3'-desphenyl-3'-(isobutenyl)-N-desbenzoyl-N-(t-butoxycarbonyl)-10-desacetoxytaxol

To a solution of 7-O-triethylsilyl-10-desacetoxy baccatin (III) (50.0mg, 0.077 mmol) in 0.8 mL of THF at -45° C. was added dropwise 0.09 mLof a 0.98 M solution of LiN(SiMe₃)₂ in hexane. After 0.5 h at -45° C., asolution ofcis-1-t-butoxycarbonyl-3-(2-methoxyisopropyloxy)-4-(isobutenyl)azetidin-2-one(58.0 mg, 0.193 mmol) in 0.7 mL of THF was added dropwise to themixture. The solution was warmed to 0° C. and kept at that temperaturefor 1 h before 1 mL of a 10% solution of AcOH in THF was added. Themixture was partitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 62.7 mg of amixture containing(2'R,3'S)-2'-O-(2-methoxyisopropyl)-7-O-triethylsilyl-3'-desphenyl-3'-(isobutenyl)-N-desbenzoyl-N-(t-butoxycarbonyl)-10-desacetoxytaxol and a small amount of the (2'S,3'R) isomer.

To a solution of 62.7 mg (0.059 mmol) of the mixture obtained from theprevious reaction in 3.5 mL of acetonitrile and 0.16 mL of pyridine at0° C. was added 0.55 mL of 48% aqueous HF. The mixture was stirred at 0°C. for 3 h, then at 25° C. for 13 h, and partitioned between saturatedaqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethylacetate solution gave 51.5 mg of material which was purified by flashchromatography to give 43.0 mg (95%) of3'-desphenyl-3'-(isobutenyl)-N-desbenzoyl-N-(t-butoxycarbonyl)-10-desacetoxytaxol, which was recrystallized from methanol/water.

m.p.153-155° C.; [α]²⁵ Na -56.3, (c 0.003, CHCl₃).

¹ H NMR (CDCl₃, 300 MHz) δ8.10(d, J=7.3 Hz, 2H, benzoate ortho), 7.60(m,1H, benzoate para), 7.47(m, 2H, benzoate meta), 6.15(td, J=8.5, 1.8 Hz,1H, H13), 5.69(d, J=6.9 Hz, 1H, H2), 5.32(d, J=9.2 Hz, 1H, NH), 4.93(dd,J=9.6, 1.8 Hz, 1H, H5), 4.82(d, J=8.7 Hz, 1H, Me₂ C═CH--), 4.76(td,J=8.7, 2.7 Hz, 1H, H3'), 4.37(d, J=8.7 Hz, 1H, H20α), 4.22(d, J=8.7 Hz,1H, H20β), 4.18(d, J=2.7 Hz, 1H, H2'), 4.03(d, J=7.3 Hz, 1H, H7),3.82(d, J=15.2 Hz, 1H, H10α), 3.47(m, 1H, 2'OH), 3.41(d, J=6.6 Hz, 1H,H3), 2.60(m, 1H, H6α), 2.39(m, 1H, H10β), 2.37(s, 3H, 4Ac), 2.18(s, 1H,7 OH), 2.08(m, 1H, H14α),1.78(m, 1H, H14β), 1.76(s, 3H, Me18), 1.74(s,6H, 2Me from isobuthenyl), 1.63(m, 1H, H6β), 1.36(s, 9H, 3Me t-buthoxy)1.26(s, 3H, Me17), 1.18(s, 3H, Me19), 1.15(s, 3H, Me16).

EXAMPLE 13 ##STR36## Preparation of3'-desphenyl-3'-(isobutenyl)-N-desbenzoyl-N-(t-butoxycarbonyl)-9-desoxo-10-desacetoxy-10-ketotaxol

To a solution of 7-O-triethylsilyl-9-desoxo-10-desacetoxy-10-ketobaccatin (III) (30.0 mg, 0.047 mmol) in 0.5 mL of THF at -45° C. wasadded dropwise 0.05 mL of a 0.98 M solution of LiN(SiMe₃)₂ in hexane.After 0.5 h at -45° C., a solution ofcis-1-t-butoxycarbonyl-3-(2-methoxyisopropyloxy)-4-(isobutenyl)azetidin-2-one (44.1 mg, 0.141 mmol) in 0.5 mL of THF was added dropwiseto the mixture. The solution was warmed to 0° C. and kept at thattemperature for 1 h before 1 mL of a 10% solution of AcOH in THF wasadded. The mixture was partitioned between saturated aqueous NaHCO₃ and60/40 ethyl acetate/hexane. Evaporation of the organic layer gave aresidue which was purified by filtration through silica gel to give 40.8mg of a mixture containing(2'R,3'S)-2'-O-(2-methoxyisopropyl)-7-O-triethylsilyl-3'-desphenyl-3'-(isobutenyl)-N-desbenzoyl-N-(t-butoxycarbonyl)-9-desoxo-10-desacetoxy-10-ketotaxol and a small amount of the (2'S,3'R) isomer.

To a solution of 40.8 mg (0.043 mmol) of the mixture obtained from theprevious reaction in 4 mL of acetonitrile and 0.2 mL of pyridine at 0°C. was added 0.5 mL of 48% aqueous HF. The mixture was stirred at 0° C.for 3 h, then at 25° C. for 13 h, and partitioned between saturatedaqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethylacetate solution gave 34.4 mg of material which was purified by flashchromatography to give 23.0 mg (70%) of3'-desphenyl-3'-(isobutenyl)-N-desbenzoyl-N-(t-butoxycarbonyl)-9-desoxo-10-desacetoxy-10-ketotaxol, which was recrystallized from methanol/water.

m.p.149-153° C.; [α]²⁵ Na -56.3° (c 0.0025, CHCl₃).

¹ H NMR (CDCl₃, 300 MHz) δ8.12(d, J=7.2 Hz, 2H, benzoate ortho), 7.64(m,1H, benzoate para), 7.51(m, 2H, benzoate meta), 6.12(t, J=7.5 Hz, 1H,H13), 5.95(d, J=6.2 Hz, 1H, H2), 5.30(d, J=8.9 Hz, 1H, NH), 4.94(d,J=8.2 Hz, 1H, H5), 4.88(d, J=8.9 Hz, 1H, Me₂ C═CH--), 4.79(td, J=8.9,2.4 Hz, 1H, H3'), 4.34(d, J=8.2 Hz, 1H, H20α), 4.27(dd, J=5.5, 2.7 Hz,1H, H2'), 4.19(d, J=8.2 Hz, 1H, H20β), 3.73(m, 1H, H7), 3.67(br s, 1H,2'OH), 3.13(d, J=5.1 Hz, 1H, H3), 3.12(d, J=15.7 Hz, 1H, H9α), 2.90(d,J=15.7 Hz, 1H, H9β), 2.55(m, 1H, H6α), 2.47(m, 1H, H14β), 2.32(s, 3H,4Ac), 2.28(m, 1H, H14α), 2.04(br s, 1H, 7 OH), 1.88(s, 1H, 1 OH),1.82(m, 1H, H6β), 1.79(s, 3H, Me18), 1.76(s, 6H, 2Me from isobuthenyl),1.57(s, 3H, Me16), 1.47 (s, 3H, Me19), 1.40(s, 9H, 3Me t-buthoxy)1.30(s, 3H, Me17).

EXAMPLE 14 ##STR37## Preparation of3'-desphenyl-3'-(isobutenyl)-N-desbenzoyl-N-(t-butoxycarbonyl)-7-O-acetyl-10-desacetyltaxol

To a solution of7-O-triethylsilyl-9-desoxy-9β-acetoxy-10-desacetoxy-10-keto baccatin(III) (33.0 mg, 0.047 mmol) in 0.5 mL of THF at -45° C. was addeddropwise 0.05 mL of a 0.98 M solution of LiN(SiMe₃)₂ in hexane. After0.5 h at -45° C., a solution ofcis-1-t-butoxycarbonyl-3-(2-methoxyisopropyloxy)-4-isobutenylazetidin-2-one(44.1 mg, 0.141 mmol) in 0.5 mL of THF was added dropwise to themixture. The solution was warmed to 0° C. and kept at that temperaturefor 1 h before 1 mL of a 10% solution of AcOH in THF was added. Themixture was partitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 41.9 mg of amixture containing(2'R,3'S)-2'-O-(2-methoxyisopropyl)-7-O-triethylsilyl-3'-desphenyl-3'-(isobutenyl)-N-desbenzoyl-N-(t-butoxycarbonyl)-9-desoxy-9β-acetoxy-10-desacetoxy-10-ketotaxol and a small amount of the (2'S,3'R) isomer.

To a solution of 41.9 mg (0.045 mmol) of the mixture obtained from theprevious reaction in 3.5 mL of acetonitrile and 0.15 mL of pyridine at0° C. was added 0.50 mL of 48% aqueous HF. The mixture was stirred at 0°C. for 3 h, then at 25° C. for 13 h, and partitioned between saturatedaqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethylacetate solution gave 32.4 mg of material which was stirred with 1.0 gof silica gel in 5 mL of methylene chloride at room temperature in 48hrs. The organic layer was purified by filtration through silica gel togive 26.2 mg (70%) of3'-desphenyl-3'-(isobutenyl)-N-desbenzoyl-N-(t-butoxycarbonyl)-7-O-acetyl-10-desacetyltaxol.

m.p.1136-139° C.; [α]²⁵ Na -60.2, (c 0.0025, CHCl₃).

¹ H NMR (CDCl₃, 300 MHz) δ8.10(d, J=7.3 Hz, 2H, benzoate ortho), 7.61(m,1H, benzoate para), 7.48(m, 2H, benzoate meta), 6.16(td, J=8.7, 1.8 Hz,1H, H13), 5.68(d, J=6.9 Hz, 1H, H2), 5.48(dd, J=10.5, 7.3 Hz, 1H, H7),5.33(d, J=1.8 Hz, 1H, H10), 5.32(d, J=9.2 Hz, 1H, NH), 4.94(dd, J=9.6,1.8 Hz, 1H, H5), 4.80(d, J=8.7 Hz, 1H, Me₂ C═CH--), 4.75(td, J=8.7, 2.7Hz, 1H, H3'), 4.33(d, J=8.7 Hz, 1H, H20α), 4.23(d, J=2.7 Hz, 1H, H2'),4.22(d, J=8.7 Hz, 1H, H20β), 4.01(d, J=6.9 Hz, 1H, H3), 3.98(d, J=1.8Hz, 1H, 10OH), 3.68(m, 1H, 2'OH), 2.54(m, 1H, H6α), 2.37(s, 3H, 4Ac),2.35(m, 1H, H14α), 2.01(m, 1H, H14β), 1.99(s, 3H, 7Ac), 1.98(br s, 3H,Me18), 1.93(m, 1H, H6β), 1.85(s, 3H, Me19), 1.77(s, 6H, 2Me fromisobuthenyl), 1.61(s, 1H, 7OH), 1.37(s, 9H, 3Me t-butoxy), 1.23(s, 3H,Me17), 1.10(s, 3H, Me16).

EXAMPLE 15 ##STR38## Preparation of3'-desphenyl-3'-(isobutenyl)-N-desbenzoyl-N-(t-butoxycarbonyl)-7-deshydroxytaxol

To a solution of 7-deshydroxy baccatin (III) (38.7 mg, 0.063 mmol) in0.8 mL of THF at -45° C. was added dropwise 0.08 mL of a 0.98 M solutionof LiN(SiMe₃)₂ in hexane. After 0.5 h at -45° C., a solution ofcis-1-t-butoxycarbonyl-3-(2-methoxyisopropyloxy)-4-(isobutenyl)azetidin-2-one(59.0 mg, 0.19 mmol) in 0.8 mL of THF was added dropwise to the mixture.The solution was warmed to 0° C. and kept at that temperature for 1 hbefore 1 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 43.4 mg of amixture containing(2'R,3'S)-2'-O-(2-methoxyisopropyl)-3'-desphenyl-3'-(isobutenyl)-N-desbenzoyl-N-(t-butoxycarbonyl)-7-deshydroxytaxol and a small amount of the (2'S,3'R) isomer.

To a solution of 43.4 mg (0.049 mmol) of the mixture obtained from theprevious reaction in 3.5 mL of acetonitrile and 0.15 mL of pyridine at0° C. was added 0.5 mL of 48% aqueous HF. The mixture was stirred at 0°C. for 3 h, then at 25° C. for 13 h, and partitioned between saturatedaqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethylacetate solution gave 40.2 mg of material which was purified by flashchromatography to give 34.1 mg (86%) of3'-desphenyl-3'-(isobutenyl)-N-desbenzoyl-N-(t-butoxycarbonyl)-7-deshydroxytaxol, which was recrystallized from methanol/water.

m.p.142-144° C.; [α]²⁵ Na -53.3° (c 0.0024, CHCl₃).

¹ H NMR (CDCl₃, 300 MHz) δ8.13(d, J=7.3 Hz, 2H, benzoate ortho), 7.60(m,1H, benzoate para), 7.47(m, 2H, benzoate meta), 6.41(s, 1H, H10),6.20(dd, J=9.0, 0.9 Hz, 1H, H13), 5.67(d, J=7.2 Hz, 1H, H2), 5.39(d,J=6.9 Hz, 1H, NH), 5.32(d, J=9.0 Hz, 1H, H3'), 4.93(dd, J=8.7, 2.1 Hz,1H, H5), 4.81(d, J=8.7 Hz, 1H, Me₂ C═CH--), 4.61(d, J=3.3 Hz, 1H, H2'),4.30(d, J=8.1 Hz, 1H, H20α), 4.17(d, J=8.1 Hz, 1H, H20β), 3.75(d, J=6.6Hz, 1H, H3), 3.41(m, 1H, 2'OH), 2.36(s, 3H, 4Ac), 2.33(m, 1H, H14α),2.30(m, 1H, H14β), 2.26(m, 1H, H6α), 2.08(m, 1H, H7α), 1.94(m, 1H, H6β),1.85(br s, 3H, Me18), 1.73(s, 6H, 2Me from isobuthenyl), 1.70(s, 3H,Me19), 1.66(s, 1H, 1 OH), 1.53(m, 1H, H7β), 1.41(s, 9H, 3Me t-buthoxy),1.25(s, 3H, Me16), 1.15(s, 3H, Me17).

EXAMPLE 16 ##STR39## Preparation of3'-desphenyl-3'-(isobutenyl)-N-desbenzoyl-N-(t-butoxycarbonyl)-7-deshydroxy-10-desacetoxytaxol

To a solution of 7-deshydroxy-10-desacetoxy baccatin (III) (28.7 mg,0.051 mmol) in 0.7 mL of THF at -45° C. was added dropwise 0.06 mL of a0.98 M solution of LiN(SiMe₃)₂ in hexane. After 0.5 h at -45° C., asolution ofcis-1-t-butoxycarbonyl-3-(2-methoxyisopropyloxy)-4-(isobutenyl)azetidin-2-one(47.3 mg, 0.15 mmol) in 0.7 mL of THF was added dropwise to the mixture.The solution was warmed to 0° C. and kept at that temperature for 1 hbefore 1 mL of a 10% solution of AcOH in THF was added. The mixture waspartitioned between saturated aqueous NaHCO₃ and 60/40 ethylacetate/hexane. Evaporation of the organic layer gave a residue whichwas purified by filtration through silica gel to give 40.3 mg of amixture containing(2'R,3'S)-2'-O-(2-methoxyisopropyl)-3'-desphenyl-3'-(isobutenyl)-N-debenzoyl-N-(t-butoxycarbonyl)-7-deshydroxy-10-desacetoxytaxol and a small amount of the (2'S,3'R) isomer.

To a solution of 40.3 mg (0.046 mmol) of the mixture obtained from theprevious reaction in 3.2 mL of acetonitrile and 0.15 mL of pyridine at0° C. was added 0.47 mL of 48% aqueous HF. The mixture was stirred at 0°C. for 3 h, then at 25° C. for 13 h, and partitioned between saturatedaqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethylacetate solution gave 35.2 mg of material which was purified by flashchromatography to give 24.0 mg (70%) of3'-desphenyl-3'-(isobutenyl)-N-debenzoyl-N-(t-butoxycarbonyl)-7-deshydroxy-10-desacetoxytaxol, which was recrystallized from methanol/water.

m.p.122-125° C.; [α]²⁵ Na -64.3° (c 0.0025, CHCl₃).

¹ H NMR (CDCl₃, 300 MHz) δ8.12(d, J=7.1 Hz, 2H, benzoate ortho), 7.60(m,1H, benzoate para), 7.48(m, 2H, benzoate meta), 6.11(td, J=8.1, 1.8 Hz,1H, H13), 5.68(d, J=6.9 Hz, 1H, H2), 5.23(d, J=9.9 Hz, 1H, NH), 5.12(d,J=9.9 Hz, 1H, H3'), 4.96(dd, J=9.1, 2.7 Hz, 1H, H5), 4.80(d, J=8.7 Hz,1H, Me₂ C═CH--), 4.58(dd, J=5.7, 2.1 Hz, 1H, H2'), 4.30(d, J=8.1, 1H,H20α), 4.19(d, J=8.1 Hz, 1H, H20β), 3.97(d, J=6.9 Hz, H3), 3.83(d,J=16.5, 1H, H10α), 3.33(m, 1H, H10β), 3.30(m, 1H, 2'OH), 2.39(m, 1H,H14α), 2.35(s, 3H, 4Ac), 2.26(m, 1H, H14β), 2.19(m, 1H, H6α), 2.10(m,1H, H7α), 1.95(m, 1H, H6β), 1.73(s, 3H, Me18), 1.69(s, 6H, 2Me fromisobuthenyl), 1.63(s, 3H, Me19), 1.44(m, 1H, H7β), 1.39(br. s, 1H, 1OH), 1.35(s, 9H, 3Me t-buthoxy), 1.25(s, 3H, Me16), 1.15(s, 3H, Me17).

EXAMPLE 17

Taxanes 29-4, 51-3, 54-1, 54-2, 54-3, 58-3, 58-4, 59-1, 59-2, 60-3,70-4, 68-4, 74-4, 70-1, 71-2, and 72-1 of Examples 1-16 were evaluatedin in vitro cytotoxicity activity against human colon carcinoma cellsHCT-116. Cytotoxicity was assessed in HCT116 human colon carcinoma cellsby XTT(2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazoliumhydroxide) assay (Scudiero et al, "Evaluation of a solubletetrazolium/formazan assay for cell growth and drug sensitivity inculture using human and other tumor cell lines", Cancer Res. 48:4827-4833, 1988). Cells were plated at 4000 cells/well in 96 wellmicrotiter plates and 24 hours later drugs were added and serialdiluted. The cells were incubated at 37° C. for 72 hours at which timethe tetrazolium dye, XTT, was added. A dehydrogenase enzyme in livecells reduces the XTT to a form that absorbs light at 450 nm which canbe quantitated spectrophotometrically. The greater the absorbance thegreater the number of live cells. The results are expressed as an IC₅₀which is the drug concentration required to inhibit cell proliferation(i.e. absorbance at 450 nm) to 50% of that of untreated control cells.

All compounds had an IC₅₀ of less than 0.1, indicating that they arecytotoxically active.

What I claim is:
 1. A taxane having the formula ##STR40## wherein X₁ is--OX₆, --SX₇, or --NX₈ X₉ ;X₂ is hydrogen, or substituted orunsubstituted alkyl, alkenyl, alkynyl, aryl, or heteroaryl; X₃ ishydrogen; X₄ is butenyl; X₅ is --COX₁₀, --COOX₁₀, --COSX₁₀, --CONX₈ X₁₀,or --SO₂ X₁₁ ; X₆ is hydrogen, or substituted or unsubstituted alkyl,alkenyl, alkynyl, aryl, or heteroaryl, or hydroxy protecting group, or afunctional group which increases the water solubility of the taxanederivative; X₇ is substituted or unsubstituted alkyl, alkenyl, alkynyl,aryl, or heteroaryl, or sulfhydryl protecting group; X₈ is hydrogen, orsubstituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, orheteroaryl, or heterosubstituted alkyl, alkenyl, alkynyl, aryl orheteroaryl; X₉ is an amino protecting group; X₁₀ is substituted orunsubstituted alkyl, alkenyl, alkynyl, aryl, or heteroaryl, orheterosubstituted alkyl, alkenyl alkynyl, aryl or heteroaryl; X₁₁ issubstituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, orheteroaryl, or --OX₁₀, or --NX₈ X₁₄ ; X₁₄ is hydrogen, or substituted orunsubstituted alkyl, alkenyl, alkynyl, aryl, or heteroaryl; R₁ ishydroxy, protected hydroxy or together with R₁₄ forms a carbonate; R₂ ishydrogen, hydroxy, --OCOR₃₁, or together with R_(2a) forms an oxo;R_(2a) is hydrogen or taken together with R₂ forms an oxo; R₄ ishydrogen, or together with R_(4a) forms an oxo, oxirane or methylene;R_(4a) is hydrogen, or substituted or unsubstituted alkyl, alkenyl,alkynyl, aryl, or heteroaryl, or cyano, hydroxy, --OCOR₃₀, or togetherwith R₄ forms an oxo, oxirane or methylene; R₅ is hydrogen or togetherwith R_(5a) forms an oxo; R_(5a) is hydrogen, hydroxy, protectedhydroxy, acyloxy, or together with R₅ forms an oxo; R₆ is hydrogen, orsubstituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, orheteroaryl, or hydroxy, protected hydroxy or together with R_(6a) formsan oxo; R_(6a) is hydrogen, or substituted or unsubstituted alkyl,alkenyl, alkynyl, aryl, or heteroaryl, or hydroxy, protected hydroxy ortogether with R₆ forms an oxo; R₇ is hydrogen or together with R_(7a)forms an oxo; R_(7a) is hydrogen, halogen, protected hydroxy, --OR₂₈, ortogether with R₇ forms an oxo; R₉ is hydrogen or together with R_(9a)forms an oxo; R_(9a) is hydrogen, hydroxy, protected hydroxy, acyloxy,or together with R₉ forms an oxo; R₁₀ is hydrogen or together withR_(10a) forms an oxo; R_(10a) is hydrogen, --OCOR₂₉, hydroxy, orprotected hydroxy, or together with R₁₀ forms an oxo; R₁₄ is hydrogen,or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, orheteroaryl, or hydroxy, protected hydroxy or together with R₁ forms acarbonate; R_(14a) is hydrogen, or substituted or unsubstituted alkyl,alkenyl, alkynyl, aryl, or heteroaryl; R₂₈ is hydrogen, acyl, hydroxyprotecting group or a functional group which increases the solubility ofthe taxane derivative; and R₂₉, R₃₀, and R₃₁ are independently hydrogen,or substituted or unsubstituted alkyl, alkenyl, alkynyl, monocyclic arylor monocyclic heteroaryl.
 2. A pharmaceutical composition which containsthe taxane of claim 1 and one or more pharmacologically acceptable,inert or physiologically active diluents or adjuvants.
 3. The taxane ofclaim 1 wherein X₃ is isobutenyl.
 4. The taxane of claim 1 wherein R₁ ishydroxy.
 5. The taxane of claim 1 wherein R₂ is benzoyloxy, and R_(2a)is hydrogen.
 6. The taxane of claim 1 wherein R_(4a) is acetoxy.
 7. Thetaxane of claim 1 wherein R₆ and R_(6a) are hydrogen.
 8. The taxane ofclaim 1 wherein R₇ is hydrogen, and R_(7a) is hydroxy or protectedhydroxy.
 9. The taxane of claim 1 wherein R_(9a) together with R₉ formsan oxo.
 10. The taxane of claim 1 wherein R₁₀ is hydrogen; and R_(10a)is acetoxy, hydroxy, or protected hydroxy.
 11. The taxane of claim 1wherein R₁₄ and R_(14a) are hydrogen.
 12. The taxane of claim 1 whereinX₁ is --OX₆ ; X₂ is hydrogen or alkyl; and X₆ is hydrogen or hydroxyprotecting group.
 13. The taxane of claim 1 whereinR₁ is hydroxy; R_(2a)is hydrogen, and R₂ is --OCOR₃₁ ; R_(4a) is --OCOR₃₀ ; R₆ and R_(6a) arehydrogen; R₇ is hydrogen, and R_(7a) is hydroxy or protected hydroxy;R_(9a) together with R₉ forms an oxo; R₁₀ is hydrogen, and R_(10a) is--OCOR₂₉, hydroxy, or protected hydroxy; R₁₄ and R_(14a) are hydrogen;R₂₉ and R₃₀ are independently substituted or unsubstituted alkyl; andR₃₁ is substituted or unsubstituted monocyclic aryl.
 14. The taxane ofclaim 12 whereinR₁ is hydroxy; R_(2a) is hydrogen, and R₂ is --OCOR₃₁ ;R_(4a) is --OCOR₃₀ ; R₆ and R_(6a) are hydrogen; R₇ is hydrogen, andR_(7a) is hydroxy or protected hydroxy; R_(9a) together with R₉ forms anoxo; R₁₀ is hydrogen, and R_(10a) is --OCOR₂₉, hydroxy, or protectedhydroxy; R₁₄ and R_(14a) are hydrogen; R₂₉ and R₃₀ are independentlysubstituted or unsubstituted alkyl; and R₃₁ is substituted orunsubstituted monocyclic aryl.
 15. The taxane of claim 14 wherein R₂ isbenzoyloxy.
 16. The taxane of claim 14 wherein R_(4a) and R₂₉ areacetoxy.
 17. The taxane of claim 1 wherein X₅ is benzoyl ort-butoxycarbonyl.
 18. The taxane of claim 1 wherein R₁ together with R₁₄forms a carbonate.
 19. The taxane of claim 1 wherein R₃₁ is hydrogen, orsubstituted or unsubstituted alkyl, alkenyl, alkynyl, or monocyclicheteroaryl.
 20. The taxane of claim 1 wherein R₃₀ is hydrogen, orsubstituted or unsubstituted alkenyl, alkynyl, monocyclic aryl ormonocyclic heteroaryl.
 21. The taxane of claim 1 wherein R₉ is hydrogen,and R_(9a) is hydrogen, hydroxy, protected hydroxy, or acyloxy.
 22. Thetaxane of claim 1 wherein R₇ is hydrogen or together with R_(7a) formsan oxo; R_(7a) is hydrogen, halogen, --OR₂₈, or together with R₇ formsan oxo; and R₂₈ is acyl or a functional group which increases thesolubility of the taxane derivative.
 23. The taxane of claim 1 whereinR₁₀ is hydrogen or together with R_(10a) forms an oxo; and R_(10a) ishydrogen or together with R₁₀ forms an oxo.
 24. The taxane of claim 1wherein R₁₄ is substituted or unsubstituted alkyl, alkenyl, alkynyl,aryl, or heteroaryl, hydroxy, protected hydroxy or together with R₁forms a carbonate.
 25. A taxane having the formula ##STR41## wherein X₁is --OX₆, --SX₇, or --NX₈ X₉ ;X₂ is hydrogen, or substituted orunsubstituted alkyl, alkenyl, alkynyl, aryl, or heteroaryl; X₃ ishydrogen; X₄ is butenyl; X₅ is --COX₁₀, --COOX₁₀, --COSX₁₀, --CONX₈ X₁₀,or --SO₂ X₁₁ ; X₆ is hydrogen, or substituted or unsubstituted alkyl,alkenyl, alkynyl, aryl, or heteroaryl, or hydroxy protecting group; X₇is substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, orheteroaryl, or sulfhydryl protecting group; X₈ is hydrogen, orsubstituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, orheteroaryl; X₉ is an amino protecting group; X₁₀ is substituted orunsubstituted alkyl, alkenyl, alkynyl, aryl, or heteroaryl; X₁₁ issubstituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, orheteroaryl, or --OX₁₀, or --NX₈ X₁₄ ; X₁₄ is hydrogen, or substituted orunsubstituted alkyl, alkenyl, alkynyl, aryl, or heteroaryl; R₁ ishydroxy, protected hydroxy or together with R₁₄ forms a carbonate; R₂ ishydrogen, hydroxy, or --OCOR₃₁ ; R_(2a) is hydrogen; R₄ is hydrogen, ortogether with R_(4a) forms an oxo, oxirane or methylene; R_(4a) ishydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl,or heteroaryl, or cyano, hydroxy, --OCOR₃₀, or together with R₄ forms anoxo, oxirane or methylene; R₅ is hydrogen or together with R_(5a) formsan oxo; R_(5a) is hydrogen, hydroxy, protected hydroxy, acyloxy, ortogether with R₅ forms an oxo; R₆ and R_(6a) are hydrogen; R₇ ishydrogen; R_(7a) is hydrogen, halogen, protected hydroxy, or --OR₂₈ ; R₉is hydrogen or together with R_(9a) forms an oxo; R_(9a) is hydrogen,hydroxy, protected hydroxy, acyloxy, or together with R₉ forms an oxo;R₁₀ is hydrogen or together with R_(10a) forms an oxo, R_(10a) ishydrogen, --OCOR₂₉, hydroxy, or protected hydroxy, or together with R₁₀forms an oxo; R₁₄ is hydrogen, hydroxy, protected hydroxy or togetherwith R₁ forms a carbonate; R_(14a) is hydrogen; and R₂₈ is hydrogen,acyl, or hydroxy protecting group; and R₂₉, R₃₀ and R₃₁ areindependently hydrogen, or substituted or unsubstituted alkyl, alkenyl,alkynyl, monocyclic aryl or monocyclic heteroaryl.
 26. The taxane ofclaim 25 wherein X₃ is isobutenyl.
 27. The taxane of claim 25 wherein X₁is --OX₆ ; X₂ is hydrogen or alkyl; and X₆ is hydrogen or hydroxyprotecting group.
 28. The taxane of claim 1 wherein:R₄ is hydrogen, ortogether with R_(4a) forms an oxo, oxirane or methylene; R₄ is hydrogen,hydroxy, alkyl, or together with R₄ forms an oxo, oxirane or methylene;R₅ is hydrogen; R_(5a) is hydrogen, hydroxy, protected hydroxy oracyloxy; and R₃₀ is as defined in claim
 1. 29. The taxane of claim 25wherein:R₄ is hydrogen, or together with R_(4a) forms an oxo, oxirane ormethylene; R₄ is hydrogen, hydroxy, alkyl, or together with R₄ forms anoxo, oxirane or methylene; R₅ is hydrogen; R_(5a) is hydrogen, hydroxy,protected hydroxy or acyloxy; and R₃₀ is as defined in claim 25.